Nuestros investigadores

Maria Arechederra Calderon

Dpto de Hepatología
Centro de Investigación Médica Aplicada (CIMA). Fundación para la Investigación Médica Aplicada
Líneas de investigación
Cáncer, Hepatología, Epigenética
Índice H
6, (WoS, 20/02/2019)

Publicaciones científicas más recientes (desde 2010)

Autores: Urtasun, R.; Elizalde, M.; et al.
ISSN 0305-1048  Vol. 47  Nº 7  2019  págs. 3450 - 3466
Genome instability is related to disease development and carcinogenesis. DNA lesions are caused by genotoxic compounds but also by the dysregulation of fundamental processes like transcription, DNA replication and mitosis. Recent evidence indicates that impaired expression of RNA-binding proteins results in mitotic aberrations and the formation of transcription-associated RNA-DNA hybrids (R-loops), events strongly associated with DNA injury. We identify the splicing regulator SLU7 as a key mediator of genome stability. SLU7 knockdown results in R-loops formation, DNA damage, cell-cycle arrest and severe mitotic derangements with loss of sister chromatid cohesion (SCC). We define a molecular pathway through which SLU7 keeps in check the generation of truncated forms of the splicing factor SRSF3 (SRp20) (SRSF3-TR). Behaving as dominant negative, or by gain-of-function, SRSF3-TR impair the correct splicing and expression of the splicing regulator SRSF1 (ASF/SF2) and the crucial SCC protein sororin. This unique function of SLU7 was found in cancer cells of different tissue origin and also in the normal mouse liver, demonstrating a conserved and fundamental role of SLU7 in the preservation of genome integrity. Therefore, the dowregulation of SLU7 and the alterations of this pathway that we observe in the cirrhotic liver could be involved in the process of hepatocarcinogenesis.
Autores: Fan, Y.; Bazai, S. K; Daian, F.; et al.
ISSN 1600-0641  Vol. 70  Nº 3  2019  págs. 470 - 482
BACKGROUND & AIMS: The variety of alterations found in hepatocellular carcinoma (HCC) makes the identification of functionally relevant genes and their combinatorial actions in tumorigenesis challenging. Deregulation of receptor tyrosine kinases (RTKs) is frequent in HCC, yet little is known about the molecular events that cooperate with RTKs and whether these cooperative events play an active role at the root of liver tumorigenesis. METHODS: A forward genetic screen was performed using Sleeping Beauty transposon insertional mutagenesis to accelerate liver tumour formation in a genetic context in which subtly increased MET RTK levels predispose mice to tumorigenesis. Systematic sequencing of tumours identified common transposon insertion sites, thus uncovering putative RTK cooperators for liver cancer. Bioinformatic analyses were applied to transposon outcomes and human HCC datasets. In vitro and in vivo (through xenografts) functional screens were performed to assess the relevance of distinct cooperative modes to the tumorigenic properties conferred by RTKs. RESULTS: We identified 275 genes, most of which are altered in patients with HCC. Unexpectedly, these genes are not restricted to a small set of pathway/cellular processes, but cover a large spectrum of cellular functions, including signalling, metabolism, chromatin remodelling, mRNA degradation, proteasome, ubiquitination, cell cycle regulation, and chromatid segregation. We validated 15 tumour suppressor candidates, as shRNA-mediated targeting confers tumorigenicity to RTK-sensitized cells, but not to cells with basal RTK levels. This demonstrates that the context of enhanced RTK levels is essential for their action in tumour initiation. CONCLUSION: Our study identifies unanticipated genetic interactions underlying gene cooperativity with RTKs in HCC. Moreover, these results show how subtly increased levels of wild-type RTKs provide a tumour permissive cellular environment allowing a large spectrum of deregulated mechanisms to initiate liver cancer. LAY SUMMARY: Receptor tyrosine kinases (RTKs) are among signals frequently deregulated in patients with hepatocellular carcinoma and their deregulation confers essential biological properties to cancer cells. We have applied a genetic method to randomly mutate large numbers of genes in the context of a mouse model with increased RTK levels, predisposed to develop liver cancer. We identified mechanisms that accelerate tumour formation in cooperation with enhanced RTK levels. The wide array of cellular functions among these cooperators illustrates an extraordinary capability of RTKs to render the liver more vulnerable to additional alterations, by priming cells for tumour initiation.
Autores: Colyn, L.; Alvarez-Sola, G.; Latasa, María Ujué; et al.
ISSN 0168-8278  Vol. 70  Nº Supl. 1  2019  págs. E27 - E28
Autores: Shan, Z. ; Alvarez-Sola, G.; Uriarte, Iker; et al.
ISSN 2305-5839  Vol. 6  Nº 12  2018  págs. 257
Currently there are very few pharmacological options available to treat acute liver injury. Because its natural exposure to noxious stimuli the liver has developed a strong endogenous hepatoprotective capacity. Indeed, experimental evidence exposed a variety of endogenous hepatic and systemic responses naturally activated to protect the hepatic parenchyma and to foster liver regeneration, therefore preserving individual's survival. The fibroblast growth factor (FGF) family encompasses a range of polypeptides with important effects on cellular differentiation, growth survival and metabolic regulation in adult organisms. Among these FGFs, FGF19 and FGF21 are endocrine hormones that profoundly influence systemic metabolism but also exert important hepatoprotective activities. In this review, we revisit the biology of these factors and highlight their potential application for the clinical management of acute liver injury.
Autores: Arechederra, Maria; Ávila, Matías Antonio; et al.
ISSN 2415-1289  Vol. 3  Nº 84  2018 
Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide. HCCs are molecularly heterogeneous tumors, and this complexity is to a great extent responsible for their poor response to conventional and targeted therapies. In this review we summarize recent evidence indicating that imbalanced expression of mRNA splicing factors can be a relevant source for this heterogeneity. We also discuss how these alterations may play a driver role in hepatocarcinogenesis by impinging on the general hallmarks of cancer. Considering the natural history of HCC, we focused on two pathogenic features that are characteristic of liver tumors: chromosomal instability and phenotypic de-differentiation. We highlight mechanisms connecting splicing derangement with these two processes and the enabling capacities acquired by liver cells along their neoplastic transformation. A thorough understanding of the alterations in the splicing machinery may also help to identify new HCC biomarkers and to design novel therapeutic strategies.
Autores: Sequera, C.; Vázquez-Carballo, A.; Arechederra, Maria; et al.
ISSN 1097-4652  Vol. 233  Nº 2  2018  págs. 968 - 978
TWEAK regulates multiple physio-pathological processes in fibroblasts such as fibrosis. It also induces migration and invasion in tumors and it can activate p38 MAPK in various cell types. Moreover, p38¿ MAPK promotes migration and invasion in several cancer cells types and in mouse embryonic fibroblasts (MEFs). However, it remains unknown if TWEAK could promote migration in fibroblasts and whether p38¿ MAPK might play a role. Our results reveal that TWEAK activates ERKs, Akt, and p38¿/ß MAPKs and reduces secreted Fibulin 3 in MEFs. TWEAK also increases migration and invasion in wt and p38¿ deficient MEFs, which indicates that p38¿ MAPK is not required to mediate these effects. In contrast, ERKs inhibition significantly decreases TWEAK-induced migration and Fibulin 3 knock-down mimics TWEAK effect. These results indicate that both ERKs activation and Fibulin 3 down-regulation would contribute to mediate TWEAK pro-migratory effect. In fact, the additional regulation of ERKs and/or p38ß as a consequence of Fibulin 3 decrease might be also involved in the pro-migratory effect of TWEAK in MEFs. In conclusion, our studies uncover novel mechanisms by which TWEAK would favor tissue repair by promoting fibroblasts migration.
Autores: Arechederra, Maria; Daian, F.; Yim, A. ; et al.
ISSN 2041-1723  Vol. 9  Nº 1  2018  págs. 3164
Epigenetic modifications such as aberrant DNA methylation reshape the gene expression repertoire in cancer. Here, we used a clinically relevant hepatocellular carcinoma (HCC) mouse model (Alb-R26Met) to explore the impact of DNA methylation on transcriptional switches associated with tumorigenesis. We identified a striking enrichment in genes simultaneously hypermethylated in CpG islands (CGIs) and overexpressed. These hypermethylated CGIs are located either in the 5'-UTR or in the gene body region. Remarkably, such CGI hypermethylation accompanied by gene upregulation also occurs in 56% of HCC patients, which belong to the "HCC proliferative-progenitor" subclass. Most of the genes upregulated and with hypermethylated CGIs in the Alb-R26Met HCC model undergo the same change. Among reprogrammed genes, several are well-known oncogenes. For others not previously linked to cancer, we demonstrate here their action together as an "oncogene module". Thus, hypermethylation of gene body CGIs is predictive of elevated oncogene levels in cancer, offering a novel stratification strategy and perspectives to normalise cancer gene dosages.
Autores: Fan, Y. ; Arechederra, Maria; Richelme, S.; et al.
ISSN 1527-3350  Vol. 66  Nº 5  2017  págs. 1644 - 1661
Genetic mutations leading to oncogenic variants of receptor tyrosine kinases (RTKs) are frequent events during tumorigenesis; however, the cellular vulnerability to nononcogenic RTK fluctuations has not been characterized. Here, we demonstrated genetically that in the liver subtle increases in wild-type Met RTK levels are sufficient for spontaneous tumors in mice (Alb-R26Met ), conceptually illustrating how the shift from physiological to pathological conditions results from slight perturbations in signaling dosage. By analyzing 96 different genes in a panel of tumor samples, we demonstrated that liver tumorigenesis modeled by Alb-R26Met mice corresponds to a subset of hepatocellular carcinoma (HCC) patients, thus establishing the clinical relevance of this HCC mouse model. We elucidated the regulatory networks underlying tumorigenesis by combining a phosphokinome screen with bioinformatics analysis. We then used the signaling diversity results obtained from Alb-R26Met HCC versus control livers to design an "educated guess" drug screen, which led to the identification of new, deleterious synthetic lethal interactions. In particular, we report synergistic effects of mitogen-activated protein kinase kinase, ribosomal S6 kinase, and cyclin-dependent kinase 1/2 in combination with Bcl-XL inhibition on a panel of liver cancer cells. Focusing on mitogen-activated protein kinase kinase and Bcl-XL targeting, we mechanistically demonstrated concomitant down-regulation of phosphorylated extracellular signal-regulated kinase and myeloid cell leukemia 1 levels. Of note, a phosphorylated extracellular signal-regulated kinase+/BCL-XL+ /myeloid cell leukemia 1+ signature, deregulated in Alb-R26Met tumors, characterizes a subgroup of HCC patients with poor prognosis. CONCLUSION: Our genetic studies highlight the heightened vulnerability of liver cells to subtle changes in nononcogenic RTK levels, allowing them to acquire a molecular profile that facilitates the full tumorigenic program; furthermore, our outcomes uncover new synthetic lethal interactions as potential therapies for a cluster of HCC patients. (Hepatology 2017;66:1644-1661).
Autores: Priego, N.; Arechederra, Maria; Sequera, C.; et al.
ISSN 1949-2553  Vol. 7  Nº 29  2016  págs. 45060 - 45078
C3G, a Guanine nucleotide Exchange Factor (GEF) for Rap1 and R-Ras, has been shown to play important roles in development and cancer. Previous studies determined that C3G regulates cell death through down-regulation of p38¿ MAPK activity. Here, we found that C3G knock-down in MEFs and HCT116 cells promotes migration and invasion through Rap1-mediated p38¿ hyper-activation. These effects of C3G were inhibited by Rap1 knock-down or inactivation. The enhanced migration observed in C3G depleted HCT116 cells was associated with reduction in E-cadherin expression, internalization of ZO-1, actin cytoskeleton reorganization and decreased adhesion. We also found that matrix metalloproteases MMP2 and MMP9 are involved in the pro-invasive effect of C3G down-regulation. Additionally, our studies revealed that both C3G and p38¿ collaborate to promote growth of HCT116 cells in vitro and in vivo, possibly by enhancing cell survival. In fact, knocking-down C3G or p38¿ individually or together promoted cell death in vitro, although only the double C3G-p38¿ silencing was able to increase cell death within tumors. Notably, we found that the pro-tumorigenic function of C3G does not depend on p38¿ or Rap1 activation. Altogether, our studies uncover novel mechanisms by which C3G controls key aspects of tumorigenesis.
Autores: Lamballe, F.; Toscano, S.; Conti, F. ; et al.
ISSN 1949-2553  Vol. 7  Nº 46  2016  págs. 74747 - 74767
The cytoplasmic tyrosine kinase ABL exerts positive or negative effects in solid tumours according to the cellular context, thus functioning as a "switch modulator". The therapeutic effects of drugs targeting a set of signals encompassing ABL have been explored in several solid tumours. However, the net contribution of ABL inhibition by these agents remains elusive as these drugs also act on other signalling components. Here, using glioblastoma (GBM) as a cellular paradigm, we report that ABL inhibition exacerbates mesenchymal features as highlighted by down-regulation of epithelial markers and up-regulation of mesenchymal markers. Cells with permanent ABL inhibition exhibit enhanced motility and invasive capabilities, while proliferation and tumorigenic properties are reduced. Intriguingly, permanent ABL inhibition also interferes with GBM neurosphere formation and with expression of stemness markers in sphere-cultured GBM cells. Furthermore, we show that the molecular and biological characteristics of GBM cells with impaired ABL are reversible by restoring ABL levels, thus uncovering a remarkable plasticity of GBM cells to ABL threshold. A phospho-signalling screen revealed that loss of tumorigenic and self-renewal properties in GBM cells under permanent ABL inhibition coincide with drastic changes in the expression and/or phosphorylation levels of multiple signalling components. Our findings identify ABL as a crucial player for migration, invasion, proliferation, tumorigenic, and stem-cell like properties of GBM cells. Taken together, this work supports the notion that the oncogenic role of ABL in GBM cells is associated with its capability to coordinate a signalling setting that determines tumorigenic and stem-cell like properties.
Autores: Arechederra, Maria; Priego, N. ; Vázquez-Carballo, A. ; et al.
ISSN 1083-351X  Vol. 290  Nº 7  2015  págs. 4383 - 4397
p38 MAPKs regulate migration and invasion. However, the mechanisms involved are only partially known. We had previously identified fibulin 3, which plays a role in migration, invasion, and tumorigenesis, as a gene regulated by p38¿. We have characterized in detail how p38 MAPK regulates fibulin 3 expression and its role. We describe here for the first time that p38¿, p38¿, and p38¿ down-regulate fibulin 3 expression. p38¿ has a stronger effect, and it does so through hypermethylation of CpG sites in the regulatory sequences of the gene. This would be mediated by the DNA methylase, DNMT3A, which is down-regulated in cells lacking p38¿, but once re-introduced represses Fibulin 3 expression. p38¿ through HuR stabilizes dnmt3a mRNA leading to an increase in DNMT3A protein levels. Moreover, by knocking-down fibulin 3, we have found that Fibulin 3 inhibits migration and invasion in MEFs by mechanisms involving p38¿/ß inhibition. Hence, p38¿ pro-migratory/invasive effect might be, at least in part, mediated by fibulin 3 down-regulation in MEFs. In contrast, in HCT116 cells, Fibulin 3 promotes migration and invasion through a mechanism dependent on p38¿ and/or p38ß activation. Furthermore, Fibulin 3 promotes in vitro and in vivo tumor growth of HCT116 cells through a mechanism dependent on p38¿, which surprisingly acts as a potent inducer of tumor growth. At the same time, p38¿ limits fibulin 3 expression, which might represent a negative feed-back loop.
Autores: Arechederra, Maria; Carmona, R. ; González-Nuñez, M.; et al.
ISSN 0925-4439  Vol. 1832  Nº 12  2013  págs. 2204 - 2215
Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-¿-MHC mouse line (referred to as ¿-MHCMet-KO). Although ¿-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as ß-MHC and ANF, was also observed. By the age of 9 months, ¿-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in ¿-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-ß production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in ¿-MHCMet-KO mice. Consistently, we show that HGF acts through p38¿ to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.
Autores: Gutiérrez-Uzquiza, A. ; Arechederra, Maria; Bragado, P.; et al.
ISSN 0021-9258  Vol. 287  Nº 4  2012  págs. 2632 - 2642
We reveal a novel pro-survival role for mammalian p38alpha in response to H(2)O(2), which involves an up-regulation of antioxidant defenses. The presence of p38alpha increases basal and H(2)O(2)-induced expression of the antioxidant enzymes: superoxide-dismutase 1 (SOD-1), SOD-2, and catalase through different mechanisms, which protects from reactive oxygen species (ROS) accumulation and prevents cell death. p38alpha was found to regulate (i) H(2)O(2)-induced SOD-2 expression through a direct regulation of transcription mediated by activating transcription factor 2 (ATF-2) and (ii) H(2)O(2)-induced catalase expression through regulation of protein stability and mRNA expression and/or stabilization. As a consequence, SOD and catalase activities are higher in WT MEFs. We also found that this p38alpha-dependent antioxidant response allows WT cells to maintain an efficient activation of the mTOR/p70S6K pathway. Accordingly, the loss of p38alpha leads to ROS accumulation in response to H(2)O(2), which causes cell death and inactivation of mTOR/p70S6K signaling. This can be rescued by either p38alpha re-expression or treatment with the antioxidants, N-acetyl cysteine, or exogenously added catalase. Therefore, our results reveal a novel homeostatic role for p38alpha in response to oxidative stress, where ROS removal is favored by antioxidant enzymes up-regulation, allowing cell survival and mTOR/p70S6K activation.
Autores: Gutiérrez-Herrero, S.; Maia, V. ; Gutiérrez-Berzal, J. ; et al.
ISSN 0167-4889  Vol. 1823  Nº 8  2012  págs. 1366 - 1377
We have generated mouse transgenic lineages for C3G (tgC3G) and C3G¿Cat (tgC3G¿Cat, C3G mutant lacking the GEF domain), where the transgenes are expressed under the control of the megakaryocyte and platelet specific PF4 (platelet factor 4) gene promoter. Transgenic platelet activity has been analyzed through in vivo and in vitro approaches, including bleeding time, aggregation assays and flow cytometry. Both transgenes are expressed (RNA and protein) in purified platelets and megakaryocytes and do not modify the number of platelets in peripheral blood. Transgenic C3G animals showed bleeding times significantly shorter than control animals, while tgC3G¿Cat mice presented a remarkable bleeding diathesis as compared to their control siblings. Accordingly, platelets from tgC3G mice showed stronger activation in response to platelet agonists such as thrombin, PMA, ADP or collagen than control platelets, while those from tgC3G¿Cat animals had a lower response. In addition, we present data indicating that C3G is a mediator in the PKC pathway leading to Rap1 activation. Remarkably, a significant percentage of tgC3G mice presented a higher level of neutrophils than their control siblings. These results indicate that C3G plays an important role in platelet clotting through a mechanism involving its GEF activity and suggest that it might be also involved in neutrophil development.
Autores: Gutiérrez-Uzquiza, A. ; Arechederra, Maria; Molina, I.; et al.
ISSN 1873-3913  Vol. 22  Nº 3  2010  págs. 533 - 542
We present here evidences supporting a negative regulation of p38alpha MAPK activity by C3G in MEFs triggered by stress, which can mediate cell death or survival depending on the stimuli. Upon serum deprivation, C3G induces survival through inhibition of p38alpha activation, which mediates apoptosis. In contrast, in response to H2O2, C3G behaves as a pro-apoptotic molecule, as its knock-down or knock-out enhances survival through up-regulation of p38alpha activation, which plays an anti-apoptotic role under these conditions. Moreover, the C3G target, Rap-1, plays an opposite role, also through regulation of p38alpha MAPK activity. Our data also suggest that changes in the protein levels of some members of the Bcl-2 family could account for the regulation of cell death by C3G and/or Rap-1 through p38alpha MAPK. Bim/Bcl-xL ratio appears to be important in the regulation of cell survival, both upon serum deprivation and in response to H2O2. In addition, the increase in BNIP-3 levels induced by C3G knock-down in wt cells treated with H2O2 might play a role preventing cell death. Therefore, we can conclude that C3G is a negative regulator of p38alpha MAPK in MEFs, while Rap-1 is a positive regulator, but both, through the regulation of p38alpha activity, can promote cell survival or cell death depending on the stimuli.


Formación académica y científica en la UCM: Me licencié en Farmacia por la UCM en Junio de 2008. Me incorporé al laboratorio de la Dra. Almudena Porras (Dpto. de Bioquímica y Biología Molecular II, Facultad de Farmacia, UCM) en el último curso la Licenciatura gracias a una Beca de colaboración concedida por el Ministerio de Educación (MEC). Posteriormente, comencé mi formación predoctoral gracias a una Beca FPU del MEC. Durante este periodo realicé dos estancias cortas en laboratorios extranjeros: 1) Laboratorio del Dr. M. Kazanietz (Department of Pharmacology, School of Medicine, Pennsylvania University, Philadelphia, USA) en 2013, gracias a una ayuda de estancias breves de la Beca FPU; 2) Laboratorio del Dr. F. Maina (IBDM, Developmental Biology Institute of Marseille, France) en 2014 gracias a una Beca EMBO (short-term). Todo esto me permitió la realización de un Doctorado Europeo en Bioquímica, Biología Molecular y Biomedicina (Marzo 2011-Diciembre 2014). "Nuevos mediadores de las acciones de p38alpha MAPK en la supervivencia y la migración/invasión celular. Interacción con C3G". Sobresaliente cum laude. Premio de la Real Academia de Doctores. Premio Extraordinario de Doctorado. Etapa postdoctoral en el IBDM: En febrero de 2015 comencé mi etapa postdoctoral en el IBDM en el laboratorio del Dr. Flavio Maina, gracias a una beca de la "Fondation de France" de 3 años. Además, durante el segundo año conseguí 25.000 euros para la realización de experimentos. Mi investigación se centró en identificar nuevas combinaciones farmacológicas para el tratamiento del carcinoma hepatocelular y en explorar la remodelación epigenética asociada al proceso hepatocarcinogénico. Durante este período, he publicado 4 artículos científicos en revistas internacionales de factores de alto impacto (2 como primer autor). Además, soy co-inventora de una patente para un nuevo biomarcador de carcinoma hepatocelular. Tengo un artículo relacionado con la patente en revisión en JCI. Durante esta etapa postdoctoral dirigí el trabajo de fin de Master (Master1 y 2) de 5 estudiantes. En 2016 obtuve el premio de la ciudad de Marsella para investigadores extranjeros. Investigadora en el CIMA: En marzo de 2018 me incorporé al Departamento de Hepatología de CIMA, dirigido por el Prof. Matías A. Ávila. He recibido una ayuda postdoctoral de la "Fundación Científica aecc" (vigente) y un contrato Juan de la Cierva (renuncia). Además, he conseguido financiación del Departamento de Salud del Gobierno de Navarra, para comenzar una nueva línea de investigación independiente centrada en la identificación de nuevos biomarcadores epigenéticos en ADN plasmático para las enfermedades hepáticas. Actualmente soy co-directora de dos estudiantes de doctorado y un trabajo fin de grado. He participado en numerosos congresos nacionales e internacionales y regularmente participo en actividades de divulgación científica.